Diastereoselective preparation of novel tetrahydrooxazinones via heterocycloaddition of N-Boc, O-Me-acetals

Article abstract of DOI:10.1016/j.tetlet.2004.10.154

Under Lewis acid conditions, reaction of N-Boc, O-Me acetals with the (R)-(+)-O-vinyl-pantolactone does not lead to the expected dihydrooxazine, but to the corresponding tetrahydrooxazinone, as a result of the loss of the t-Bu group. A diastereoselective

Full text of DOI:10.1016/j.tetlet.2004.10.154

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9589–9592
Diastereoselective preparation of novel tetrahydrooxazinones via
heterocycloaddition of N-Boc, O-Me-acetals
*
´
Patricia Gizecki, Ramzi Ait Youcef, Celine Poulard, Robert Dhal and Gilles Dujardin
´ ´ ´
Unite de Chimie Organique Moleculaire et Macromoleculaire, UMR 6011 CNRS Universite du Maine,
72085 Le Mans Cedex 9, France
´
Received 10 September 2004; revised 27 October 2004; accepted 27 October 2004
Available online 11 November 2004
Abstract—Under Lewis acid conditions, reaction of N-Boc, O-Me acetals with the (R)-(+)-O-vinyl-pantolactone does not lead to the
expected dihydrooxazine, but to the corresponding tetrahydrooxazinone, as a result of the loss of the t-Bu group. A diastereoselec-
tive and asymmetrical way to these new heterocyclic compounds is described, together with the first evidence of their ability to
undergo N-acylation.
Ó 2004 Elsevier Ltd. All rights reserved.
The enantioselective synthesis of protected b-aminoalde-
hydes is of specific interest in the chemistry of b-peptides
derivatives. More particularly, N-protected b-aminoal-
dehydes 1 (Scheme 1) are key intermediates in order to
prepare reduced peptides1 and ꢀcarbaꢁ peptides.2 As a
new development of b-aminoaldehyde chemistry, it
would then be interesting to consider getting access to
C-terminal b-peptide aldehydes 2 (b-PAs). C-Terminal
peptides aldehydes 3 (PAs) display important biological
activities as inhibitors of proteolytic enzymes3 (Aspartic:
HIV protease, renin; cysteinic: cathepsins). For this
purpose, we considered if PAs homologues 2 could be
obtained via C-protected derivatives of b-aminoalde-
hydes 1.
a dihydrooxazine 4 that is asymmetrically obtained by
heterocycloaddition of (R)-O-vinyl pantolactone 5 with
a N-benzoyl benzaldimine 6 or its synthetic equivalent,
the N, O-acetal 7,4 in the presence of a Lewis acid cata-
lyst (Yb(fod)3) or promoter (SnCl4) (Scheme 2).
Considering that N-protected b-aminoaldehydes 1 with
a N-Boc protecting group would be even more interest-
ing for the present project, we next experimented this
pathway with new N-Boc-protected cycloreactants. We
report here that under similar reaction conditions, both
N-Boc benzaldimine 8a5 and N-Boc, O-Me acetal 9a do
not lead to the expected dihydrooxazine, but to the
tetrahydrooxazinone 10a, as a result of the loss of the
t-Bu group (Scheme 3). The tetrahydrooxazinone
10a thus obtained is representative of a novel class of
We have recently disclosed an enantioselective route to
b-benzamidoaldehydes 1 (P = Bz) via the hydrolysis of
Scheme 1.
Keywords: Oxazinones; N,O-Acetals; Asymmetric synthesis; Pantolac-
tone; Chiral vinyl ether.
*
Corresponding author. Tel.: +33 243833344; fax: +33 243833902;
e-mail: dujardin@univ-lemans.fr
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.154

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P. Gizecki et al. / Tetrahedron Letters 45 (2004) 9589–9592
The extension of the cycloaddition method in order to
get variably substituted 4-aryl and 4-alkyl tetrahydroox-
azinones 10 required the preparation of N-Boc imines 8
or of various N-Boc, O-Me acetals 9 obtained through
the corresponding sulfones 13 (Scheme 4, Table 2).
The sulfones 13a–g were prepared in satisfactory yields
using the Engbertsꢁ method,8 with the exception of the
sulfone 13e which was prepared by the Petriniꢁs meth-
od.9 The elimination reaction of the sulfones 13 with
the Kanazawaꢁs method5 gave heterogeneous results.
Scheme 3.
The conditions used (K2CO3, THF, reflux) to get the N-
Boc imines 8 were satisfactory only when applied to the
aryl substrates 13a (R = Ph) and 13b (R = p-MeO–Ph).
Under these conditions, 13d (R = Bn) underwent isome-
rization and gave 14, 13e (R = t-Bu) was converted into
the bis-carbamate 15, 13f (R = p-NO2–Ph) remained un-
changed and the 13g (R = thiazolyl) was degraded. Be-
cause of the difficulties we had to get an access to the
imines 8, we favoured the preparation of N-Boc, O-Me
acetals 9 that can be easily obtained via basic methano-
lysis of the corresponding sulfones 13 (Scheme 4, Table
2).
heterocyclic compounds6 that are very promising as pre-
cursors enabling the peptide-like coupling of the amine
function of a C-protected b-aminoaldehyde 1. In this re-
port, we describe convenient conditions to obtain vari-
ous tetrahydrooxazinones 10 in a diastereoselective
and asymmetrical way, and we show that it is possible
to convert such heterocycles into N-acylated derivatives
(e.g., 11, 12).
A preliminary study, conducted on 8a and 9a allowed us
to know how to determine the influence of the Lewis
acid on the reactivity and the stereochemical outcome
of the reaction (Scheme 3, Table 1). Contrariwise to its
N-benzoyl equivalent 6, the N-Boc imine 8a displays
no reactivity towards vinyl ether 5 in the presence of a
catalytic amount of Yb(fod)3 (entry 1). Clean formation
of the tetrahydrooxazinone 10a was observed when
using one equivalent of SnCl4 at low temperature (entry
3). The conversion into 10a proved to be incomplete, but
highly stereoselective: the exclusive formation of exo-b
and endo-b diastereoisomers was thus observed.7 Better
conversions into 10a were obtained when using stoichi-
ometric amounts of BF3ÆEt2O at higher temperatures
(entries 4 and 5), but in these cases the facial selectivity
decreased and a significant degradation of the imine 8a
was observed. When starting from the more stable N-
Boc, O-Me acetal 9a at À40°C, the conversion was com-
plete with one equivalent of TMSOTf (entry 6), but the
facial selectivity proved to be higher when using
BF3ÆEt2O or SnCl4 (entries 7 and 8). Optimal conditions
were finally reached using 1.1equiv of SnCl4 at À40°C
(entry 9).
Scheme 4. Reagents and conditions: (i) t-Bu carbamate, sodium
benzenesulfinate, formic acid, methanol (THF for 13e), water, rt; (ii)
K2CO3, THF, reflux; (iii) MeONa, MeOH.
Table 1. Formation of the tetrahydrooxazinone 10a under various Lewis acid conditions
8–9a
Catalyst (equiv/5)
T °C (time)
% Conv.
10a/5d
Diastereomeric distribution of 10ac
% Yieldd
10a-exo-b
exo-b
endo-b
exo-a
endo-a
b
1
2
3
4
5
6
7
8
9
8a
8a
8a
8a
8a
9a
9a
9a
9a
Yb(fod)3 (0.05)
Yb(OTf)3 (0.05)
SnCl4 (1)
0
0
0–reflux (2d)
À78 (15min)
À40(1h 30min)
À18 (15min)
À40(1h 30min)
À40(1h 30min)
À40(1h 30min)
À40(1h)
66
87
13
00
5
BF3ÆOEt2 (1)
BF3ÆOEt2 (1)
TMSOTf (1)
BF3ÆOEt2 (1)
SnCl4 (1)
81
100
95
84
3
2
0
64
10
2.5
0
100
86
93
95
93
6
5.5
93
91
5
4
2
1
e
e
67
SnCl4 (1.1)
100
6
1
0
70
a 5 (1equiv), 8a or 9a (1.1equiv) in CH2Cl2, otherwise noted.
b Cyclohexane, reflux, 3d; toluene, reflux, 1d.
c By 1H NMR.
d After chromatography on SiO2.

P. Gizecki et al. / Tetrahedron Letters 45 (2004) 9589–9592
Table 2. Preparation of N-Boc, O-Me acetals 9 and imines 8
9591
reaction to the thiazolyl N, O-acetal 9g (R = 1,3-thiazo-
lyl) seemed promising since the corresponding adduct,
bearing two orthogonally-protected aldehyde groups10
could lead to useful derivatives of aspartic aldehyde.
Unfortunately, no reaction occurred in this case.
R
13 % Yield
9
% Yield
8
% Yield
Ph
aa
b
c
79
66
85
89
65
75
58
a
b
c
d
e
f
98
78
79
89
75
94
84
aa 98
p-MeO–Ph
p-CF3–Ph
Ph–CH2
t-Bu
b
c
d
e
f
87
—
0b
0c
0d
0e
d
e
Moreover, in order to evaluate the ability to N-acylate
these new compounds, standard N-benzoylation condi-
tions were tested on the crude intermediate tetrahydro-
oxazinones 10a and b (Scheme 6).After chromatographic
purification, the N-benzoylated products 11a (R = Ph)
and 11b (R = p-MeO–Ph) were isolated as pure single
exo-b isomers in good overall yields (85 and 70%,
respectively). Alternatively, the N-Boc derivative 12a
was conveniently obtained in 60% yield starting from
the exo-b adduct 10a.
p-NO2–Ph
1,3-Thiazol-2-yl
f
g
g
g
a See Ref. 5.
b Isomerization of 8d into the enecarbamate 14 (88%).
c Exclusive formation of bis-carbamate 15.
d No reaction.
e Degradation.
Thanks to the optimized conditions for the preparation
of the tetrahydrooxazinone 10a (Table 1, entry 9), the
analogous compounds 10b–e were conveniently ob-
tained from the corresponding N-Boc, O-Me acetals 9
(Scheme 5, Table 3). The cycloaddition reaction was
conducted in the presence of SnCl4 at À40°C for the ad-
ducts 10b–c, and at À78°C for the more sensitive sub-
strates 10d (R = Bn) and 10e (R = t-Bu), leading
homogeneously to satisfactory conversions (74–100%).
However, given the relative instability of adducts 10
on silica gel, the yields of isolated products were in most
cases notably lower than those expected on the basis of
the conversion rates. In all cases, the preferential forma-
tion of the exo-diastereoisomers and a high b-facial
selectivity (P98/2) were observed. Application of this
The absolute configuration of the tetrahydrooxazinone
10a thus obtained from the (R)-O-vinyl pantolactone
5
11 (Table 3, entry 1) was determined after chemical cor-
relation with aldehyde (R)-1a (Scheme 6).4 The crude N-
benzoyl tetrahydrooxazinone 11a was directly submitted
to hydrolysis in acidic medium, and the aldehyde 1a was
isolated after chromatography (24% overall yield from 5
1
and 9a). On the basis of the H NMR analysis in the
presence of a chiral shift reagent ((+)-Eu(tfc)3 30
mol%), the b-benzamidoaldehyde (R)-1a thus identified4
Scheme 6. Reagents and conditions: (i) benzoyl chloride, Et3N, 4-
DMAP, CH2Cl2, rt; (ii) 6M HCl, THF, rt; (iii) Boc2O, Et3N, 4-DMAP,
dichloromethane, 0°C.
Scheme 5. Reagents and conditions: (i) SnCl4, CH2Cl2, low tempe-
rature.
Table 3. Diastereoselective access to tetrahydrooxazinones 10a–e
R
10
T °C
Conversiona
10/5
Diastereomeric distribution of 10b
% Yieldc
10-exo-b
exo-b
endo-b
70
exo-a
endo-a
Ph
a
0
À401093
À4088
À4074
À78
6
91
94
1
0
p-MeO–Ph
p-CF3–Ph
Ph–CH2
t-Bu
b
7
2
0
60
c
6
e
034
0
d
100
180090
0
93
—
6
1
18
0
e
—
À78
e
—
030
—
1,3-Thiazol-2-yl
À40
—
a 5 (1equiv), 9 (1.1equiv), SnCl4 (1.1equiv), dichloromethane, 1h.
b Determined by 1H NMR (%) of the crude product.
c Isolated yields of pure exo-b isomer after chromatography on SiO2.

9592
P. Gizecki et al. / Tetrahedron Letters 45 (2004) 9589–9592
with a 97% ee allowed us to confirm the b facial feature
of the starting tetrahydrooxazinone 10a.
References and notes
1. Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994,
50, 9457.
2. (a) Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron
Lett. 1990, 31, 5153; (b) Rodriguez, M.; Heitz, A.;
Martinez, J. Tetrahedron Lett. 1990, 31, 7319; (c) Llinares,
In conclusion, the present study has demonstrated the
synthetic usefulness of SnCl4 as a promoting Lewis acid
for the asymmetrical synthesis of a novel class of tetra-
hydrooxazinones of type 10. As the preparation of N-
Boc imines 8 does not show any general feature, the
use of new N-Boc, O-Me acetals 9 precursors, easily ob-
tained from the corresponding sulfones 13, was exempli-
fied. The heterocyclic reaction of these N, O-acetals 9
with the (R)-O-vinyl pantolactone 5 led to the formation
of the tetrahydrooxazinones 10a–e with a high b facial
selectivity (P98/2). The ability of these heterocyclic
compounds to undergo N-acylation was demonstrated
by the easy conversion of 10a into its corresponding
N-benzoyl and N-Boc derivatives. Extension of this
methodology to the synthesis of other N-acylated com-
pounds is in progress in our laboratory, one main pro-
ject being the access by this pathway12 to C-terminal
b-peptide aldehydes 2.
´
M.; Devin, C.; Azay, J.; Berge, G.; Fehrentz, J. A.;
Martinez, J. Eur. J. Med. Chem. 1997, 32, 767.
3. Fehrentz, J. A.; Paris, M.; Heitz, A.; Velek, J.; Winternitz,
F.; Martinez, J. J. Org. Chem. 1997, 62, 6792, and
references cited therein.
4. (a) Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org.
Lett. 2000, 2, 585; (b) Gizecki, P.; Dhal, R.; Poulard, C.;
Gosselin, P.; Dujardin, G. J. Org. Chem. 2003, 68, 4338.
5. Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org.
Chem. 1994, 59, 1238.
6. The relevant literature seems restricted to a recent
synthesis of a N-butyl 6-acyloxy tetrahydrooxazinone via
[4+2] cycloaddition of a N-acyliminium ion generated by
electrochemical oxidation: Suga, S.; Nagaki, A.; Tsutsui,
Y.; Yoshida, J. Org. Lett. 2003, 2, 945.
7. Diastereoisomeric distribution was determined in 1H
NMR by comparison with previously observed data of
dihydrooxazine 4a (R = Ph).4 As a typical example of the
correlations that can be established between 1H diastereo-
topic signals of compounds 4a and 10a, the chemical shifts
of the N, O-acetalic protons H-6 are in the following
range: d endo-b > d exo-a > d exo-b.
Acknowledgements
We would like to thank Simon Bazolo and Nicolas de
Veaublanc for the preparation of the sulfones 13 and
of the N-Boc, O-Me acetals 9.
8. Engberts, J. B. F. N.; Strating, J. Recl. Trav. Chim. 1965,
84, 842.
9. Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970.
10. (a) Altman, L. J.; Richheimer, S. L. Tetrahedron Lett.
1971, 12, 4709; (b) Dondoni, A.; Marra, A.; Perrone, D.
J. Org. Chem. 1993, 58, 275.
11. The (R)-(+)-O-vinyl-pantolactone 5 used in this study
was found to have 98.5% ee (determined by chiral GC).4b
12. Conversion of 10a into 1a via 11a can be considered as a
model of N-trans-acylation that could be extended to a/b-
aminoacid-type N-coupling reagents.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2004.10.154. Experimental procedures, characteriza-
tion and spectroscopic assignment for representative
compounds 8–13.